Methamphetamine (MA) and related stimulant abuse remains a major public health concern globally. MA addiction is a highly complicated neuropathological disorder that recruits multiple brain regions and neurotransmitter systems. Despite decades of research, no effective pharmacotherapy has yet been developed for treating MA addiction. Imidazoline I2 receptors may represent a novel target for developing pharmacotherapy of drug addiction. Accumulating evidence indicates that I2 receptor agonists can modulate the dopaminergic system and behavioral studies have demonstrated the attenuation of the addiction-related effects of opioids by the endogenous imidazoline receptor ligand agmatine. However, little is known of whether pharmacologically selective I2 receptor ligands modulate the addiction-related effects of drugs of abuse. We recently observed that a selective I2 receptor agonist, 2-BFI, markedly attenuates MA induced behavioral sensitization and conditioned place preference. The objective of the present application is to evaluate the proof-of-concept that the I2 receptor is a novel drug target for the treatment of MA addiction. Guided by exciting preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) examine the effect of an I2 receptor agonist, 2-BFI, and an antagonist, tracizoline, on the development and reinstatement of MA-induced conditioned place preference (Aim 1); 2) examine the interaction between I2 receptor ligands and MA in animals discriminating MA or the I2 receptor agonist, 2-BFI, using a drug discrimination procedure (Aim 2). Collectively, the proposed studies systematically evaluate the effects of I2 receptor ligands on the addiction- related (e.g., rewarding and discriminative stimulus) effects of MA. These data will provide valuable information regarding the potential therapeutic value of I2 receptor agonists for the treatment of addiction to MA and related stimulants. In addition, data obtained in the proposed investigation may contribute to the identification of further novel I2 receptor based pharmacotherapies for addiction to MA.